Smad4-expression is decreased in breast cancer tissues: a retrospective study

Background  

Although transforming growth factor β (TGF-β) typically inhibits proliferation of epithelial cells, consistent with a tumor suppressor activity, it paradoxically also exhibits pro-metastatic activity in the later stages of carcinogenesis. Since tumors often display altered TGF-β signaling, particularly involving the Smad-pathway, we investigated the role of Smad4-expression in breast cancer.     

Loss of Smad4 in colorectal cancer induces resistance to 5-fluorouracil through activating Akt pathway

Background:

Higher frequency of Smad4 inactivation or loss of expression is observed in metastasis of colorectal cancer (CRC) leading to unfavourable survival and contributes to chemoresistance. However, the molecular mechanism of how Smad4 regulates chemosensitivity of CRC is unknown.

Methods:

We evaluated how the loss of Smad4 in CRC enhanced chemoresistance to 5-fluorouracil (5-FU) using two CRC cell lines in vitro and in vivo. Immunoblotting with cell and tumour lysates and immunohistochemical analyses with tissue microarray were performed.

Results:

Knockdown or loss of Smad4 induced tumorigenicity, migration, invasion, angiogenesis, metastasis, and 5-FU resistance. Smad4 expression in mouse tumours regulated cell-cycle regulatory proteins leading to Rb phosphorylation. Loss of Smad4 activated Akt pathway that resulted in upregulation of anti-apoptotic proteins, Bcl-2 and Bcl-w, and Survivin. Suppression of phosphatidylinositol-3-kinase (PI3K)/Akt pathway by {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002 restored chemosensitivity of Smad4-deficient cells to 5-FU. Vascular endothelial growth factor-induced angiogenesis in Smad4-deficient cells might also lead to chemoresistance. Low levels of Smad4 expression in CRC tissues correlated with higher levels of Bcl-2 and Bcl-w and with poor overall survival as observed in immunohistochemical staining of tissue microarrays.

Conclusion:

Loss of Smad4 in CRC patients induces resistance to 5-FU-based therapy through activation of Akt pathway and inhibitors of this pathway may sensitise these patients to 5-FU.     

Phase II trial of sorafenib in combination with 5-fluorouracil infusion in advanced hepatocellular carcinoma

Abstract  

     

Genistein downregulates onco-miR-1260b and upregulates sFRP1 and Smad4 via demethylation and histone modification in prostate cancer cells

Background:

Recently several microRNAs (miRNAs) have been found to be regulated by genistein in cancer cells. In this study, we focused on the gene regulatory effect of genistein on microRNA and its target genes in prostate cancer (PC).

Methods:

Initially, we investigated the effect of genistein on prostate cancer cells and identified that the expression of miRNA-1260b was decreased by genistein. We performed functional analyses and investigated the relationship between miRNA-1260b expression and prostate cancer patient outcomes. Two target genes (sFRP1 and Smad4) of miR-1260b were identified based on computer algorithm and 3′UTR luciferase assay was carried out to determine direct miRNA regulation of the genes.

Results:

Genistein promoted apoptosis while inhibiting prostate cancer cell proliferation, invasion and TCF reporter activity in PC cells. MiR-1260b was highly expressed in prostate cancer tissues and significantly downregulated by genistein in PC cells. After knocking down miR-1260b, cell proliferation, invasion, migration and TCF reporter activity were decreased in PC cells. Western analysis and 3′UTR luciferase assay showed that the two target genes (sFRP1 and Smad4) were directly regulated by miR-1260b. The expression of sFRP1 and Smad4 was significantly decreased in prostate cancer tissues. Genistein also increased expression of these two genes via DNA demethylation and histone modifications.

Conclusions:

Our data suggest that genistein exerts its anti-tumour effect via downregulation of miR-1260b that targeted sRRP1 and Smad4 genes in prostate cancer cells. The expression of sFRP1 and Smad4 was also modulated by genistein via DNA methylation or histone modifications in PC cell lines.     

What factors affect the odds of NSW cancer patients presenting with localised as opposed to more advanced cancer?

Abstract  

     

Adherence to the 2018 World Cancer Research Fund/American Institute for Cancer Research Cancer Prevention Recommendations and cancer risk: A systematic review and meta-analysis

Background

The World Cancer Research Fund/American Institute for Cancer Research Cancer Prevention Recommendations are lifestyle-based guidelines that aim to reduce cancer risk. A systematic review and meta-analysis of studies investigating associations between a score for adherence to the 2018 Cancer Prevention Recommendations and cancer risk was conducted.

Methods

MEDLINE, Embase, Web of Science, and Scopus were searched for studies published to November 28, 2022. In meta-analysis, the estimated risk ratios and 95% CIs for adherence score as a continuous (per 1-point increment) and categorical (highest vs. lowest score category) variable using random-effects models were estimated.

Results

Eighteen studies (11 cohort; seven case-control) were included investigating incidence of breast (n = 7), colorectal (n = 5), prostate (n = 2), lung (n = 2), pancreatic (n = 1), endometrial (n = 1), unknown primary cancer (n = 1), chronic lymphocytic leukemia (n = 1), and overall (any) cancer (n = 1). The summary risk ratio per 1-point increment in adherence score was 0.89 (95% CI, 0.85–0.93; I² = 76.5%; n = 7) for breast cancer, 0.88 (95% CI, 0.84–0.91; I² = 26.2%; n = 4) for colorectal cancer, and 0.92 (95% CI, 0.86–0.98, I² = 66.0%; n = 2) for lung cancer. There were no significant associations with prostate or other cancers. Meta-analysis results using categorical adherence score variables were consistent with these findings.

Conclusions

Greater adherence to the 2018 World Cancer Research Fund/American Institute for Cancer Research Cancer Prevention Recommendations was associated with lower risk of breast, colorectal, and lung cancers. Future studies investigating associations with risk of other forms of cancer are warranted.

PROSPERO registration number

CRD42022313327.     

Health care costs of depression in patients diagnosed with cancer

Objective

Depression is common among patients diagnosed with cancer. Patients with cancer and depression use more health care services compared with nondepressed cancer patients. The current study seeks to estimate the added cost of depression in cancer patients in the first year after cancer diagnosis.

Methods

Health care charges were obtained for 2051 depressed and 11 182 nondepressed patients with an International Classification of Diseases, Ninth Revision, diagnosis of cancer in the 2014 calendar year from the University of California San Diego Healthcare System. The annual health care charges for cancer patients with and without depression were analyzed using generalized linear models with a log‐link function and gamma distribution, covarying for age, sex, race/ethnicity, comorbid diseases, and presence of metastatic disease. Total cost data were broken down into several categories including ambulatory care, emergency department visits, and hospital visits.

Results

Depressed cancer patients had total annual health care charges that were 113% higher than nondepressed cancer patients (B = 0.76; P < .001). The estimated mean charges for depressed patients were $235 337 compared with $110 650 for nondepressed patients. Depressed cancer patients incurred greater charges than nondepressed patients in ambulatory care (B = 0.70; P < .001), emergency department charges (B = 0.31; P < .001), and hospital charges (B = 0.39; P < .001).

Conclusions

Depressed cancer patients incur significantly higher health care charges across multiple cost categories including ambulatory care, emergency department visits, and hospital visits. Future research should investigate if interventions for detecting and treating depression are effective for reducing health care use and costs in cancer patients.

     

Multivariate analysis of immunohistochemical evaluation of protein expression in pancreatic ductal adenocarcinoma reveals prognostic significance for persistent Smad4 expression only

Background

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis with a 5-year survival rate of <5% and an average survival of only 6?months. Although advances have been made in understanding the pathogenesis of PDAC in the last decades, overall survival has not changed. Various clinicopathological and immunohistological variables have been associated with survival time but the exact role that these variables play in relation to survival is not clear.

Methods and results

To examine how the variables affected survival independently, multivariate analysis was conducted in a study group of 78 pancreatic ductal adenocarcinomas. The analysis included clinicopathological parameters and protein expression examined by immunohistochemistry of p53, Smad4, Axl, ALDH, MSH2, MSH6, MLH1 and PMS2. Lymph node ratio <0.2 (p?=?0.004), tumor free resection margins (p?=?0.044) and Smad4 expression (p?=?0.004) were the only independent prognostic variables in the multivariate analysis. Expression of the other proteins examined was not significantly related to survival.

Conclusions

Discrepancies with other studies in this regard are likely due to differences in quantification of immunohistochemical staining and the lack of multivariate analysis. It underscores the importance to standardize the methods used for the application of immunohistochemistry in prognostic studies.     

Anti-tumor efficacy of gene vaccine expressing PSMA

Objective  

To observe anti-tumor eff ects of PVAX-PSMA gene vaccine.     

Spontaneous regression of bone metastasis from renal cell carcinoma; A case report

Background  

Spontaneous regression of metastatic renal cell carcinoma is rarely observed.     

Prospective evaluation of the drug-metabolizing enzyme polymorphisms and toxicity profile of docetaxel in Korean patients with operable lymph node-positive breast cancer receiving adjuvant chemotherapy

Background  

Inter-individual variability of pharmacokinetics may account for unpredictable toxicities of docetaxel.     

VEGF-A-independent and angiogenesis-dependent tumour growth in patients with metastatic breast cancer

Background  

The mechanisms of tumour progression during anti-VEGF-A treatment are poorly understood.     

Circulating tumor DNA-based molecular residual disease detection for treatment monitoring in advanced melanoma patients

Background

Immune checkpoint inhibitors (ICIs) have substantially improved overall survival in patients with advanced melanoma; however, the lack of biomarkers to monitor treatment response and relapse remains an important clinical challenge. Thus, a reliable biomarker is needed that can risk-stratify patients for disease recurrence and predict response to treatment.

Methods

A retrospective analysis using a personalized, tumor-informed circulating tumor DNA (ctDNA) assay on prospectively collected plasma samples (n = 555) from 69 patients with advanced melanoma was performed. Patients were divided into three cohorts: cohort A (N = 30), stage III patients receiving adjuvant ICI/observation; cohort B (N = 29), unresectable stage III/IV patients receiving ICI therapy; and cohort C (N = 10), stage III/IV patients on surveillance after planned completion of ICI therapy for metastatic disease.

Results

In cohort A, compared to molecular residual disease (MRD)-negative patients, MRD-positivity was associated with significantly shorter distant metastasis-free survival (DMFS; hazard ratio [HR], 10.77; p = .01). Increasing ctDNA levels from the post-surgical or pre-treatment time point to after 6 weeks of ICI were predictive of shorter DMFS in cohort A (HR, 34.54; p < .0001) and shorter progression-free survival (PFS) in cohort B (HR, 22; p = .006). In cohort C, all ctDNA-negative patients remained progression-free for a median follow-up of 14.67 months, whereas ctDNA-positive patients experienced disease progression.

Conclusion

Personalized and tumor-informed longitudinal ctDNA monitoring is a valuable prognostic and predictive tool that may be used throughout the clinical course of patients with advanced melanoma.     

8q24 sequence variants in relation to prostate cancer risk among men of African descent: A case-control study

Background  

Human chromosome 8q24 has been implicated in prostate tumorigenesis.     

Trabectedin has a low cardiac risk profile: a comprehensive cardiac safety analysis

Purpose  

This analysis provides a cross-study evaluation of the cardiac safety of trabectedin.